Up to one half of older patients with major depression develop Late-Life Treatment Resistant Depression (LLTRD). Consequences of LL-TRD include suicide, worsened medical conditions, increased caregiver burden, and higher all-cause mortality. The development and testing of novel-mechanism pharmacotherapies is a public health priority embraced by NIMH. Among the neuropeptidergic transmitters, opioids are known to modulate mood, and this system is often altered in patients with major depression. Targeting the opiate system in LL-TRD may positively modulate a system in which there is age-associated imbalance between circulating opiates and the density and binding affinity of mu and kappa opiate receptors. Buprenorphine (BPN) is an antagonist at the kappa opiate receptor and a partial agonist at the mu opiate receptor. Either, or both, of these pharmacodynamic actions may underlie its putative antidepressant effects. Our research group has open pilot data from 15 older adults with prospectively demonstrated treatment resistance to venlafaxine who were exposed to low-dose BPN, suggesting a clinically meaningful antidepressant effect. In addition, since BPN: 1) is available in sublingual formulation and 2) has a favorable safety and pharmacokinetic profile, it is an attractive candidate to re-purpose as a molecule for LL-TRD. Thus, the overarching aims of this amended application for a Collaborative R34 Pilot Study of Innovative Treatments in Mental Disorders (PA-12-071) are to examine the feasibility, safety, tolerability and clinical effect of low-dose BPN as a novel treatment for LL-TRD and to develop preliminary data about mechanism of action (MOA). The three collaborative sites include Pittsburgh (coordinating site), Toronto (CAMH), and Washington University (St. Louis). Across the 3 sites, we will utilize a clinical trial that establishes treatment resistance prospectively prior to 10 weeks of double-blind, randomized, placebo-controlled exposure to low-dose BPN. Shared feasibility aims are to: a) randomize 30 subjects at each of the three sites; and b) collect BPN and metabolite plasma levels on all 90 subjects to explore a dose-effect relationship on treatment response. MOA study methods unique to each site are: 1) Neuroreceptor PET study of opiate receptors before and after exposure to BPN/placebo in 30 subjects to demonstrate pharmacodynamic MOA at our dosing range (St. Louis); 2) fMRI study in 30 subjects comparing activation in the limbic system and reward circuits before and after BPN/placebo exposure to examine neurocircuitry-level MOA (Pittsburgh); and 3) transcranial magnetic stimulation study of cortical inhibition deficits (a neurophysiological proxy for dysfunctional GABA-ergic neurotransmission) in 30 subjects before and after BPN/placebo exposure to examine neurophysiological MOA (Toronto). These findings will be scientifically integrated by the team, and are an efficient response to the novel-mechanism treatment development priorities of NIMH as described in the 2008 Strategic Plan and the 2010 Council Report From Discovery to Cure.